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Spotted: RIPK3 and MLKL assembling necroptotic complexes

Verónica Martínez-Osorio1, Uris Ros2, Ana J García-Sáez1,2

  • 1CECAD Cluster of Excellence Cluster at the University of Cologne , Cologne, North Rhine-Westphalia, Germany.

Open Biology
|January 27, 2026
PubMed

Insights

Necroptosis, a regulated cell death pathway, involves RIPK1, RIPK3, and MLKL signaling. This review explores the structure and regulation of the RIPK3-MLKL axis, crucial for cell death execution.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Necroptosis is a regulated cell death (RCD) pathway crucial for host defense against pathogens.
  • It is distinct from caspase-dependent RCD and relies on RIPK1, RIPK3, and MLKL signaling.
  • The RIPK3-MLKL interaction forms the necrosome, mediating cell death execution.

Purpose of the Study:

  • To review the current understanding of necroptosis, focusing on the RIPK3-MLKL axis.
  • To elucidate the structural organization and regulatory mechanisms governing MLKL interaction with RIPK3.
  • To discuss models of necrosome assembly and activation, addressing unresolved questions.

Main Methods:

  • Literature review of existing research on necroptosis.
  • Analysis of structural data concerning MLKL and RIPK3 interactions.
  • Synthesis of current knowledge on necrosome formation and regulation.

Main Results:

  • The RIPK3-MLKL axis is central to necroptosis execution.
  • Structural features of MLKL influence its binding to RIPK3.
  • The high-order assembly of the necrosome and its dynamic states are not fully understood.

Conclusions:

  • Further research is needed to fully resolve the structural basis and regulation of the RIPK3-MLKL interaction.
  • Understanding necrosome assembly dynamics is key to comprehending necroptosis.
  • This review consolidates current knowledge and highlights future research directions in necroptosis.
Keywords:
MLKLRIPK3inflammationmembrane permeabilizationnecroptosis

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